Treatment of pain, fever or inflammation with 5-fluoro-2-methyl-1-cp-methylsulfinyl-benzylidene)-3-indenylacetaldehyde

ABSTRACT

New substituted indenyl acetaldehydes, having anti-inflammatory, anti-pyretic and analgesic activity. Also included herein are methods of preparing said indenyl acetaldehydes, pharmaceutical compositions having said indenyl acetaldehydes as an active ingredient and methods of treating inflammation by administering these particular compositions to patients.

United States Patent [1 Shen et al. 1 May 13, 1975 TREATMENT OF PAIN,FEVER OR [56] References Cited INFLAMMATION UNITED STATES PATENTS3,654,349 4/1972 Shen et al 424/304 METHYLSULFlNYL-BENZYLIDENE)-3-3,720,774 3/l973 Peister et al. 424/303 INDENYLACETALDEHYDE 3,725,5484/1973 Shen et al 424/303 [75] entors g Ying S est e 3,732,292 5/1973Hinkley et al. 260/515 A H Jones Holmdel both of PrimaryExaminer-Stanley J. Friedman Attorney, Agent, or Firm-Mario A. Monaco;Harry E. [73] Assignee: Merck & (10., Inc., Rahway, NJ. Westlake, Jr.

[22] Filed: Sept. 7, 1972 57 ABSTRACT [2|] Appl. No.: 287,130 1 Newsubstituted lndenyl acetaldehydes, having anti- Related Application Datainflammatory, anti-pyretic and analgesic activity. Also [63]Continuation-impart of Ser. No. 248,291, A ril 27, included herein aremethods of preparing said indenyl I972, abandoned. acetaldehydes,pharmaceutical compositions having said indenyl acetaldehydes as anactive ingredient and [52] U.S. Cl. 424/303 methods of treatinginflammation by administering [51] Int. Cl A6lk 27/00 these particularcompositions to patients. [58] Field of Search 424/303 2 Claims, NoDrawings 1 THE TREATMENT OF PAIN, FEVER OR INFLAMMATION WITHS-FLUORO-Z-METI-IYL-l-CP-METHYLSULFINYL-BENZYLIDENE)-3-INDENYLACETALDEI-IYDE RELATED APPLICATIONS Thisapplication is a continuation-in-part of Application Ser. No. 248,291filed Apr. 27, 1972 now abandoned.

SUMMARY OF THE INVENTION Generally, this invention relates to newsubstituted indenyl acetaldehydes and processes for producing the same.This invention also relates to pharmaceutical compositions containingsaid indenyl acetaldehydes as an active ingredient and to methods oftreating pain, fever or inflammation by administering these particularcompounds to patients.

DESCRIPTION AND PREFERRED EMBODIMENTS This invention relates to newsubstituted indenyl acetaldehydes and processes for producing the same.More specifically, this invention relates to compounds having thefollowing general formula:

wherein:

R, and R each may be loweralkenyl, loweralkylthio, arylthio, amino,loweralkylamino, N-heteroaryl, alkenyloxy, alkoxycarbonyl, hydrogen,loweralkyl, haloloweralkyl, halo, acylamino, aralkoxycarbonyl,dialkylamino, hydroxy, loweralkoxy, alkynyloxy, aralkoxy, carboxy andtogether can be alkenyl or carbonyl.

R R R R R and R each may be hydrogen, alkyl, acyloxy, aryloxy, alkoxy,nitro, amino, acylamino, alkylamino, dialkylamino, alkenyl, alkynyl,alkenyloxy, dialkylaminoalkyl, sulfamyl, alkylthio, alkylsulfinyl,alkylsulfonyl, hydroxy, hydroxyalkyl, acyl, halo, cyano, carboxyl,carboalkoxy, carbamido, haloalkyl, cycloalkyl, cycloalkloxy or aroyl.

R may be hydrogen, alkyl, haloalkyl, alkenyl, alkynyl or trihalomethyl;

X may be alkylene, alkenylene, alkynylene, O, S, sulfinyl, sulfonyl orNR where R can be hydrogen or alkyl;

Ar is aryl or heteroaryl; and

n is O or 1 with the exception that when n is 0, R,, R

R,, R and R are hydrogen, R and R is methylsulfmyl and the otherhydrogen, Ar is phenyl and R is methyl, R is other than fluoro.

The compound which is excluded from the general formula above isdisclosed in Greek Pat. No. 41,736 issued Jan. 11, 1971 and correspondsto U.S. Application Ser. No. 33,890 filed May 5, 1970, still pending.The compound is described as an intermediate for preparing indenylacetic acids. We have found that this compound, however, haspharmaceutical properties as the compounds themselves claimed herein andare administered in the same manner and dosage as described hereinbelowfor the compounds of this invention. This discovery makes up anotherpart of our invention.

The aryl or heteroaryl substituent in the l-position of the indenenucleus may include an aryl ring system such as benzene, naphthalene orbiphenyl or a heteroaryl ring system such as pyrrole, furan, thiophene,pyridine, imidazole, pyrazine, thiazole, etc., and may be substitutedwith any of the aformentioned R, and R substituents.

In the most preferred compounds of this invention R, and R each may behydrogen or loweralkyl, R R R and R each may be hydrogen, halogen,loweralkoxy, loweralkyl, nitro, amino or substituted amino such asdialkylamino, alkylamino, etc., R is alkylsulfinyl, R is hydrogen, R isloweralkyl, X is alkylene or alkenylene, n is 0 or 1 and Ar is phenyl.In these preferred groups the hydro carbon chains are those whichcontain at most 5 carbon atoms. However, the substituents on the indenylacetaldehyde nucleus are not limited to the preferred class ofsubstituents and includes all those set forth in Formula I, as well asthose which are therapeutically equivalent to those which arespecifically enumerated.

Representative compounds of this invention are as follows:

S-Hydroxy-Z-methyll-(pmethylsulfinylbenzylidene)-indenyl-Ii-acetaldehyde;

5-Methoxy-2-methyl-1-(pmethylsulfinylbenzylidene)-indenyl-3-acetaldehyde;

a-[S-Fluoro-Z-methyl-l-(pmethylsulfinylbenzylidene )-3- indenelpropionaldehyde;

5 ,6-Difluoro-2-methyl- 1-(pmethylsulfinylbenzylidene)-indenyl-3-acetaldehyde;

5-Chloro-2-methyl- 1 p-methylsulfinylbenzylideneindenyl-3-acetaldehyde',

S-Trifluoromethyl-2-methyll-(pmethylsulfinylbenzylidene)-indenyl-3-fluoroacetaldehyde;

2,5-Dimethyll-( p-methylsulfinylbenzylidene )-inde' nyl-3-acetaldehyde;

5 ,7-Diflu0ro-2-methyll-(pmethylsulfinylbenzylidene)-indenyl-3-acetaldehyde;

a-[ 5,7-Difluoro-2-methyll pmethylsulfinylbenzylidene)-3-indenelpropionaldehyde;

S-Dimethylamino-6-fluoro-2-methyl- 1(3 '-fluoro-4methylsulfinylbenzylidene)-indenyl-3-acetaldehyde;

5-Methoxy-6-fluoro-Z-methyll-(pfluorobenzylidene)-indenyl-3-acetaldehyde;

a-[5Methoxy-fi-fluoro-Z-methyll-(pmethylthiobenzylidene)-3-indenelpropionaldehyde;

l-Cinnamylidenyl-5-fluoro-2-methyl-indenyl-3- acetaldehyde;

5 -Fluoro-2-methyll-(pmethylsulfinylcinnamylidene)-indenyl-3-acetaldehyde;

S-Methoxy-Z-methyll(p-chlorobenzylidene)-indenyl-3-acetaldehyde; and

S-Fluoro-Z-methyll p-methylsulfonylbenzylidene)- indenyl-3-acetaldehyde.

This invention also relates to a method of treating, pain, fever orinflammation in patients using a compound of Formula I, particularly thepreferred compounds and especiallyS-fluoro-Z-methyl-l-(pmethylsulfinylbenzylidene) indenyl-3-acetaldehydeas the active constituent.

The compounds of the instant invention can be used to treat inflammationby reducing inflammation and relieving pain in such diseases asrheumatoid arthritis, osteoarthritis, gout, infectious arthritis andrheumatic fever. The compounds of Formula I also have anti-pyretic andanalgesic activity and would be administered and used in the same mannerand in the same dosage ranges as if they were being used to treatinflammation as discussed further on.

The treatment of inflammation in accordance with the method of thepresent invention is accomplished by topically, orally, rectally orparenterally administering to patients a composition of a compound ofFormula I, particularly the especially preferred compounds in anon-toxic pharmaceutically acceptable carrier.

The non-toxic pharmaceutical carrier may be, for example, either a solidor a liquid. Exemplary of solid carriers are lactose, corn starch,gelatin, talc, sterotix, stearic acid, magnesium stearate, terra alba,sucrose, agar, pectin, cab-o-sil, and acacia. Exemplary of liquidcarriers are peanut oil, olive oil, sesame oil and water. Similarly, thecarrier or diluent may include a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax.

Several pharmaceutical forms of the therapeutically useful compositionscan be used. For example, if a solid carrier is used, the compositionsmay take the form of tablets, capsules, powders, troches or lozenges,prepared by standard pharmaceutical techniques. If a liquid carrier isused, the preparation may be in the form of a soft gelatin capsule, asyrup, an aqueous solution or a liquid suspension. Suppositories may beprepared in a conventional manner by mixing the compounds of thisinvention with a suitable non-irritating excipient which is solid atroom temperature, but liquid at the rectal temperature. Such materialsare cocoa butter and polyethylene glycol. Gels and lotions for topicalapplication may be prepared in conventional manners.

The active compounds of Formula I and of the compositions of thisinvention are administered in an amount sufficient to treatinflammation, that is to reduce inflammation. Advantageously, thecompositions will contain the active ingredient, namely, the compoundsof Formula I in an amount of from about 0.1 mg. to 50 mg. per kg. bodyweight per day (5 mg. to 3.5 g. per patient per day), preferably fromabout 1 mg. to mg./kg. body weight per day (50 mg. to l g. per patientper day).

The method of treatment of this invention comprises administering to apatient (animal or human), a com pound of Formula I, particularly anespecially preferred compound admixed with a non-toxic pharmaceuticalcarrier such as exemplified above. The compounds of Formula I andparticularly the especially preferred compounds will be administered inan amount of from 0.1 mg. to 50 mg./kg. body weight per day, preferablyfrom about 1 mg. to about 15 mg. per kilogram body weight per day. Themost rapid and effective antiinflammatory effect is obtained from oraladministration of a daily dosage of from about 1 to 15 mg./kg./day. Itshould be understood, however, that although preferred dosage ranges aregiven, the dose level for any particular patient depends upon theactivity of the specific compound employed. Also many other factors thatmodify the actions of drugs will be taken into account by those skilledin the art in the therapeutic use of medicinal agents, particularlythose of Formula I, for example, age, body weight, sex, diet, time ofadministration, route of administration, rate of excretion, drugcombination, reaction sensitivities and severity of the particulardisease.

In the preparation of the compounds of this invention the startingmaterial is a l-unsubstituted indenyl-3- acetic acid. This compound isesterified and reduced to form the corresponding alcohol. The desired 1-substituent is inserted and the alcohol is oxidized to the correspondingaldehyde.

EXAMPLE l S-Fluoro-Z-methyll (p-chlorobenzylidene)-indenyl-3-acetaldehyde A. Methyl S-fluoro-Z-methylindenyl-3-acetate5-Fluoro-2-methylindenyl-3-acetic acid (10.0 g.) is refluxed withstirring in methanol ml.) containing concentrated sulfuric acid (2 ml.)for 1 hour. The solution is evaporated to near dryness at 10C. andextracted into ether-water 10: l, 200 ml. separated and washed withsaturated sodium bicarbonate solution (2 X 50 ml.) then water again (50ml.). The ether layer is dried (MgSO,), filtered and evaporated to givethe solid ester m.p. 53.5-54.5.

Using the same reaction conditions and techniques, the following indenylesters are prepared in accordance with the procedure of Example 1A:

STARTING MATERIAL PRODUCT S-methoxy-Z-methylindenyl-3- methyl aceticacid 5-methoxy-2-methylindenyl- 3acetate 5-chloro-2-methylindenyl-3-methyl acetic acid 5-chloro-2-methylindenyl3-acetate acetic acid 5,6difluoro-Z-methylindenyl- 3-acetate S-fluoro-6-methoxy-2- methylmethylindenyl-3-acetic acid 5-fluoro-6-methoxy-2-methylindenyl-B-acetate methyl 5-cyano-2 ethylindenyl3acetate methylS-allyloxyindenyl-3-acetate 5 cyano-2-ethylindenyl-3-acetic acidS-allyloxylindenyl-3-acetic acid B. 5-Fluoro-2-methyl-idenyl-3B-ethanolThe ester in ether (75 ml.) is added with stirring over one-half hour toa suspension of lithium aluminum hydroxide (1.0 g.) in ether (50 ml.).The mixture is then refluxed for 3 hours. cooled in ice bath, methanol(50 ml.) added slowly followed by water (50 ml.). Anhy- 5 drousmagnesium sulfate is added and the mixture stirred, filtered and redriedwith magnesium sulfate. The ether solution is evaporated to give an oilwhich was chromatographed on silica-gel (200 g. Baker 60-200 mesh).Benzene elutes the desired alcohol m.p.

Using the same reaction conditions and techniques, the following indenylalcohols are prepared in accordance with the procedure of Example 18.

STARTING MATERIAL PRODUCT methyl 5-methoxy-2-methylindenyl- 3-acetatemethyl 5-chloro-2-methylindenyl- 3-acetate methyl5,e-difluordZ-methylindenyl- 3-acetate methyl 5-fluoro-6-methyoxy-2-methylindenyl-Zu-acetate methyl 5-cyano2-ethylindenyl- 3-acetate methyl5-allyloxylindenyl-B-acetate methyl 5-amino2-vinylindenyl- 3-acetatemethyl S'dimethylaminOQ methyIindenyI-Bacetate methyl5-hydroxy-2-methylindenyl- El-acetate methylG-cyclopropyl-2-methylindenyl- 3-acetate methyl5-sulfamyl-Z-methylindenyl- 3 acetate methyl pro ionateS-methoxy-Z-methyIindenyl-El-B ethanol S-chloro-2-methylindenyl-3-B-ethanol 5.6difluoro-2-methylindenyl-34 ethanol5-fluoro-6-methoxy2-methylindenylJ-B-ethanol 5-cyano-2-ethylindenyl-lflethanol 5-allyloxylindenyl-3-B-ethanol 3O5-amino-2-vinylindenyl-3'B-ethanol 5-dimethylamino-Z-methylindenyl- 3-fl-ethanol 3 5 S-hydroxy-Zmethylindenyl-3B- ethanol6-cyclopropyl-2-methylindenyl-3 -3- ethanol5-sulfamyl-Z-methylindenyl-Zv-B ethanol C. S-Fluoro-Z-methyllp-chlorobenzylidene )-indenyl-3-B-ethanol To a solution ofS-fluoro-Z-methylindenyl-3B-ethanol (1.92 g. 0.01 mole) in methanol (30ml.) is added sodium methoxide (1.08 g. 0.02 mole), and thenpchlorobenzaldehyde (0.0l mole). This solution is refluxed overnight,poured into ether water (10:1 300 ml.). the ether back washed withwater. dried (MgSO and concentrated to a yellow oil (3.4 g.) (3). Thisoil is chromatographed on silica-gel 100 g. Baker -200 mesh) and ethylacetate elutes the desired alcohol m.p.

Using the same reaction conditions and techniques, the followingl-substituted alcohols are prepared in ac- 60 cordance with theprocedure of Example lC.

STARTING MATERIAL REACTANT PRODUCT 5-methyoxy2- p-methylsulfi-5-methoxy-2-methyll pmethylindenylJ-B- ny methylsulfinylbenzylideneethanol benzaldehyde )-indenyl-3-B-ethanol -Continued STARTING MATERIALREACT ANT PRODUCT S-chloro-Z-methylindenyl-3-flethanol 5 ,6-difluoro-2-methylindenyLB-B- ethanol 5 -fluoro'6-methoxy-2-methylindenyl-S-fiethanol 5-cyano-2 ethylindenyl-3' B-ethanol5-allyloxylindenyl-3-B- ethanol 5-amino-2-vinylindenyl-3- 5dimethylamino-2- methylindenyl-3-l3 ethanol S-fluoro-Z-methylindenyl-3-B-ethanol 5-hydroxy-2-methylindenyl-3-;S-ethanol 6cyclopropyl-2-methylindenyLEl-ethanol 5-sulfamyl-2 -methylindenyl-3-l3-ethanola-(S-fluoro-Z- methylindenyl-3-propanolS-methoxy-Z-methylindenyl-3-fi-ethanol5-chloro-2-methylindenyI-S-B-ethanol p-methylsulfinylbenzaldehydep-methylsulfinylbenzaldehyde nylbenzaldehydep-methylsulfinylbenzaldehyde p-methylsulfinylbenzaldehydep-methylsulfinylbenzaldehyde p-methylsulfinylbenzaldehydep-methylsulfinylbenzaldehyde p-methylsulfinylbenzaldehyde p-methylsulfiy(pbenzaldehyde methylsulfinylbenzylidene- )-indcnyl-3-B-ethanolS-sulfamyLZ-methyl-l-(pmethylsulfinylbenzylidene- )-indenyl-3 fl-ethanola-[S-fluoro-Z-methyl-l -(pnylmethylsulfinylbenzyli benzaldehydc denel]-3-propanol p- 5-fluoro-2-methyl-l-(pmethylben methylbenzylidene)-indezaldehyde nyI-B-B-ethanol p- S-methoxy-Z-methyll -(pbenzaldehydep-methylsulfichloroben chlorobenzylidene )-indezaldehyde nyl- 3-fiethanol p-cyclopropyl- 5-chloro-2-methyll -(pbenzaldehydecyclopropylbenzylidene indenyl-3 -B-ethanol cinnamalde-Lcinnamylidene-S-fluorohyde Z-mcthylindenylJ-fi ethanol 4methylsulfi-5-fluoro-2-methyll -(pnylmethylsulfinylcinnamylidecinnamalde ne)indenyl3-/3-ethanol hyde D. nyl-3-acetaldehyde S-Fluoro-Z-methyll-(p-chlorobenzylidene )-indeacetate (0.85 gm).

Using the same reaction conditions and techniques, the following indenylacetaldehydes are prepared in accordance with the procedure of Example1D.

STARTING MATERIAL PRODUCT STARTING MATERIAL PRODUCTS-methoxyQ-methyl-l-(p 5methoxy2-methyl-l (p 56-nitr0-2-fluoromethylindanone ethylrnethylsulfinylbenzylidene)-indemethylsulfinylbenzylidene)indenyl-S-nitro-Z-fluoromethylindenyl-3 0:- nyl- 3-5-2 thanol 3 -acetaldehydefluoroacetate 5-chloro-2-methyll p- S-chloro-2-methyll p-6-nitro-Z-trifluoromethylindaethylmelhylsulfinylbenzylidene)-indemethylsulflnylbenzylidene)-indenylnone5-nitro-2-trifluoromethylindenyl-3- nyl-3-&ethanol 3-acetaldehydea-fluoroacetate 5,6-difluoro-2methyll p- S,6-difluoro-2-rnethyll p-6-tluoromethyl-2- ethylmethylsulfinylbenzylidene)indemethylsulfinylbenzylidene-indenyllmethylindanone S-fluoromethyl-2-methylindenyl-3- nyl-3-B-ethanol3-acelaldehyde a-fluoroacetate 5-fluoro-fiqnethoxyQ-methyh l5-fluoro-6-methoxy-2-methyll p- 5-benzoyl-2-methylindanone cthy(p-rnethylsulfinylbenzylidene methylsulfinylidene )-indenyl-3-ibenzoyl-Z-methylindenyl-3-mindenyl-3-B-ethanol acetaldehydefluoroacemie 5cyano2-ethyl- 1 p- 5-cyano-2-ethyll p- 5-acetyl-2- ethylmethylsulfinylbenzylidene)-indemethylsulfinylbenzylidene)-indenylfl ghli d 6 |.2 h [i d |.3. nyl-Il-B-ethanol B-acetaldehyde 1 5 flucmcewe yy- 1 P- y y y 1 P -carboethoxy-Z- ethyl methylsulfinylbenzyhdene)-mdemethylsulfinylbenzylidene)-indenylmethylindanone 5. m g m p3.nyl-Elfi-ethanol S-acetaldehyde mfluomawtate y -(P y -(p-G-carbamido-Z-trifluoromeethyl methylsulfinylbenzyhdene)indemethylsulfinylbenzylidene)-indenylh li d 5. ;b i4 .2 y -B- "9 9 ytrifluoromethylindenyl-3-0- 5-d|methylam1no-2-methyl l -(p- SdlmethylammoQ-methyll -(pfluomacemwmethylsulfinylbenzylidcneHndemethylsulfinylbenzylidene)indenyl- 5. 2ehy] y 'fi 3acelaldehyde fluoromethylindanone-carboxyl-2-fluoromethylindenyl- S-fluoro-Z-methyll p-5-fluoro-2-methyll p- 3. fl w methylsulfinylbenzylidene)-indemethylsulfinylbenzylidcne )-indenylnylJ-Bethanol 3-acetaldehyde5-hydroxy-2-methyll-(p- 5-hydr0xy-2-methyl-l-(pmethylsulfinylbenzylidene)-inde methylsulfinylbenzylidene)-indenylgy fig h l I gi yi m I 1 B. 5-N1tro-2-methylindenyl-3-a-fluoroacetic acid-cyc opropy -met y p -cyc opropy -me y p methylsulfinylbenzylidene)-indemethylsulfinylbenzylidene)-indenyl- E l5mtro'g'methylmdenyl'll'a'fluoroaqetate nyl-3f-,8-ethanol h lg-actaldeih de h I l g.) is dissolved in methanol (10 ml.) and sodiummeth- 5-sul amyl-Z-met y -1-(p- -su amy- -met y--(pmethylsulfinylbenzylidene)-indemethylsulfinylbenzylidene)-indenyloxideaddfid i wawfr l Is h nyl-3-B-ethanol 3-acetaldehyde added and after 15mm. the mixture is acidified with 'i 2.5 N. hydrochloric acid atice-bath temperatures, and methylsulfinylbenzyhdenemethylsulfinylbenzyhdene )-mdenylindenyl3-propanol 3-acetaldehydefiltered to yleld the acldi y d g i zy lgd 1 Using the same reactionconditions and techniques, igl' lgz e 222 x 34? the following indenylIl-a-fluoroacetic acids are pre 5-methoxy-2'm thyl44p-5-methoxy-2-methyl-l(p- 35 pared in accordance with the procedure ofExample chlorobenzylidene)-indenyl-3-/3- chlorobenzylidene)-indenyl-3-28 ethanol acetaldehyde S-chloro-Z-rnethyl-l-(pS-chloro-Z-methyl-l-(pcyclopropylbenzylidene-indenylcyclopropylbenzylidene)-indenyl-3-3-B-ethanol acetaldehyde l-cinnamylidene-5-fluoro-2- l-cinnamylidene-S-fluoro-2- methylidenyl-3-B-ethanol methylidenyl-3-acetaldehyde STARTINGMATERIAL PRODUCT S-fluoro-Z-methyll p- 5-fluoro-2-methyll-(pmethylsulfinylcinnamylidene)- methylsulfinylcinnamylidene)-indeethyl'q 'q d 3 l thanol n l 3 B ethanol S-nitro 2-fluoromethyhndenyl-3fluoroacetic acid m any y a-fluoroacetate ethylS'nitmZ-trifluoromethylindenyl-3- S-nitro-Z- a-fluoroacetic acidtrifluoromethylindenyl-S-afluoroacetate EXAMPLE 2 ethylS-fluoromethyl-Z-methylindenyl-Il-S-fluoromethyl-Z-methylindenyla-fluoroacetic acid i -2-meth lindenl-3-a-fluoroacetate imflumoacelale A Ethyl 5 n no y y 6 3 d h I ethyl5-benzoyl-2-methylindenyl-3a- 6Nltro'zmethylmdanone (2 8- an ct yS-benzoyl-2-methylindenyl-3-afluoroacetic acid bromofluoracetate (30.2g.) In benzene (500 ml.) are fltilolioacetate et y added slowly tozinc-amalgam (48.3 g.) and a crystal of Mmy| 2 methylindeny] 3*! lodineunder benzene (20 ml.) to promote selffluoroacetatefi-acetyl-2-methylindenyl-3-afluoroacetic acid sustaining gentle reflux.When all has been added, the ethyl 5flflmemoxyQmedwlindewb3 mixture lSrefluxed for 2 hours, cooled to 5 C. and acld- 5,carboethowimehy|indeny| fl ti acid ified with ID percent sulfuric acid.3-a-fluoroacemte t d d M so d Va rat d ethyl S-carbamido-Z- The benzeney 15 g 4 an e P e S-carbamldoltrifluoromethylmdenyl-3-0:- to give an Oilwhich iS distilled at l0O-l70 and 0.25gifluoromethylindenyl-3-afluoroacetic acid 0 o uoroacetate mm. ofpressure. The mam faction hp 142 -h44 (0.25 ethyl 6carbonfluommemynndenyl mm. 15 Z-flUOI'O-l-l1ydf0Xy-2-mIhyl-6-nltfOmCla-6.ca b xy|-2 3.a.flugr0agflc acid fluorometh linden l-3- nyl-3-acetate.an Y uoroacetale This Oil (1.0 g.) lfl benzene (50 ml.) lS stirred withphosphourous pentoxide (3.0 g.) at reflux for 15 min., cooled andfiltered. The benzene filtrate is washed with water (10 ml), separatedand dried (MgSO Evapo- C. 5-Nitro-2-methylindenyl-3-fluoroacetaldehyderation of the benzene gives the title compound.SNitro-ZmethylindenyI-3-a-flu0roacetic acid (25 Using the same reactionconditions and techniques, the following indenyl esters are prepared inaccordance with the procedure of Example 2A.

g.) is stirred in tetrahydrofuran (400 ml.) at room temperature whilethionyl chloride (12 g.) is added in benzene (10 ml.).

The solution is evaporated to dryness and the product reacted withdiethylamine solution as described in Truitt et al. J. Amer. Chem. Soc.71 3480 (1949) to give N ,N '-diethyl S-nitro-Z-methyl-S-B-fluoroacetamide.

N,N'-diethyl -nitro-2-methyI-3-B-fluoroacetamide g.) is added in drytetrohydrofuran (100 ml.) to a stirred suspension of lithiumtri-t-butoxyaluminum hydride (3.3 g.) in tetrahydrofuran (l0 ml.) over Ihour. The reaction mixture is then refluxed for 1 hour. cooled, pouredinto ice water and the furan layer separated. The organic solution isdried (MgSO and evaporated to dryness. Chromatography on silica-gel(Baker 60-200 mesh) gives the desired aldehyde.

Using the same reaction conditions and techniques, the followingaldehydes are prepared in accordance with the procedure of Example 2C.

STARTING MATERIAL PRODUCT5-nitro-2fluorornethylindenyl-34xfluoroacetaldehydeS-nitro-24rit'lu0romethylindenyI-3 a-fluoroacetaldehyde 5fluoromethyl-2-methylindenyl-3 a-fluoroacetaldehyde5-benzoyl2-methyIindenyl-Za-afluoroacetic acid fluoroacetaldehyde6-acetyl-2-methylindenyl-3-a- 6-acetyl-2-methylindenyl3-afluoroaceticacid fluoroacetaldehyde Smarboethoxy-2-methylindenyl- 3-a-fluoroaceticacid 5-carbamido-2- trifluoromethylindenyl-3-afluoroacetic acid D. Theethylene acetal protected aldehyde5-Nitro-2-methylindenyl-3-fluoroacetaldehyde (23.4 g), ethyleneglycol(6.5 g.) and p-toluene sulfonic acid (O.l g.) in benzene (200 ml.) arerefluxed for l8 hours under a Dean-Stark water trap. The benzenesolution is washed twice with water (50 ml.), dried and evaporated todryness. The product is an oil. E.S-Nitro-Z-methyl-l-(p-methylsulfinyibenzylidene)-indenyl-3-fluoroacetaldehyde-ethylene ketal The protected aldehyde (27.8g.) is reacted as described in Example I part C to give the titlecompound.

Using the same reaction conditions and techniques, the followingl-substituted indenylacetaldehydes are prepared in accordance with theprocedures of Examples 2D and 2E.

ethylene ketal -Continued STARTING MATERIAL REACIANT PRODUCT 5-benzoyl2-p-methylsul- S-benzoyl-Z-methyll-(pmethylindenyl-3-afinylbenzaldemethylsulfinylbenzylidenefluoroacetaldehydehyde )-indenyI-3- fluoroacetaldehydeethylene ketal6-acetyl-2methylindenyl p-methylsul- 6-acetyl-2-methyl-l-(p3-q-fluoroacetaldehyde finylbenzaldemethylsulfinylbenzylidene- 'hyde)-indenyl-3- fluoroacetaldehydeethylene ketal 5-carboeth0xy-2p-methylsul- S-carboethoxy-Z-methyll methylindenyLS-afinylbenzalde-(pfluoroacetaldehyde hyde methylsulfinylbenzylidene- )-indenyl-3-fluoroacetaldehydeethylene ketal S-carbamidoQ- p-methylsul-5-carbamido-2- trifluoromethylindenyl-3- finylbenzaldetrifluoromethyllpa-fluoroacetaldehyde hyde methylsulfinylbenzylidene- Hndenyl-B-fluomacetaldehydeethylene ketal fi-carboxyl-Z- p-methylsul- 6carboxyl-2-fluoromethylindenyl-3-afinylbenzaldefluoromethyll pfluoroacetaldehydehyde methylsulfinylbenzylidene )-indenyl-3 fluoroacetaldehydeethyleneketal STARTING MATERIAL PRODUCT 5 -nitro-2-fluoromethyllpmethylsulfinylbenzylidene Hndenyl- 3-fluoroacetaldehyde5-nitro-2-fluoromethyll-( pmethylsulfinylbenzylidene)-indenyl-3-fluoroacetaldehydeethylene ketal S-fluoromethyl-Z-methyll-(pmethylsulfinylbenzylidene indenyl3-fluoroacetaldehydeethylene ketal 5benzoyl-2-methyll -(pmethylsulfinylbenzylideneindenyl-3-fluoroacetaldehydeethylene ketal fi-acetyl-Z-methyl- Ipmethylsulfinylbenzylidene indenyl-3-fluoroacetaldehydeethylene ketalS-carboethoxy-Z-methyL l -(p- S-lluoromethyl-Z-methyll-(pmethylsulfinylbenzylidene)-indenyl- 3-fluoroacetaldehydeS-benzoyl-Z-methyll-(pmethylsulfinylbenzylidene)indenyl-3-fluoroacetaldehyde5-carboethoxy-2-methyl-l-(pmethylsulfinylbenzylidenemethylsulfinylbenzylidene )-indenyI indenyl-3fluoroacetaldehyde-3-fluoroacetaldehyde ethylene ketal 5-carbamido-2trifluoromethyl-I(p'methylsulfinylbenzylidene )indenyl-3-fluoroacetaldehyde EXAMPLE 35-Dimethylamino-2-methyl-l -(pmethylsulfinylbenzylidene )-indenyl-3-fluoroacetaldehyde A. p-Methylsulfinylacetophenonep-Methylthioacetophenone (16.6 g.) is stirred in acetone-water (98:2;600ml.) and sodium metaperiodate (2L4 g.) added in the minimum volume of 80water over 1 hour. At this time the acetone is evaporated off at roomtemperature and the solid pmethylsulfinylacetophenone filtered off anddried. p-Methylsulfinylphenacyl bromide To p-methylsulfinylacetophenone(18.2 g.) in glacial acetic acid (100 ml.) is added slowly 40 g. ofbromine. The mixture is vigorously shaken during the addition. when theaddition is complete the flask is cooled in ice water and the titlecompound isolated. C. p-Methylsulfinylphenylglyoxal hydrate The abovephenacyl bromide (26.0 g.) is dissolved in 100 ml. dimethyl sulfoxide atroom temperature. After 9 hours the solution is pound into ice-water andextracted with diethyl ether, the extracts are washed with water anddried via magnesium sulfate. The derived glyoxal hydrate is purified bysublimation.

. S-Dimethylarnino-Z-methyll pmethylsultinylbenzoylidene)-indenyl-3-fluoroacetaldehyde The above hydrate is reacted with S-dimethylamino-Z-methylindenyl-3-fluoroacetaldehyde ethylene ketal (as in Example 2E)and deblocked (as in Example 2F) to give the title compound.

EXAMPLE 4 A mixture of 250 parts of5-fluoro-2-methyl-l-(pmethylsulfinylbenzylidene)-3-indenylacetaldehydeand 25 parts of lactose is granulated with suitable water and to this isadded 100 parts of maize starch. The mass is passed through a l6-meshscreen. The granules are dried at a temperature below 60C. The drygranules are passed through a l6-mesh screen and mixed with 3.8 parts ofmagnesium stearate. They are then compressed into tablets suitable fororal administration according to the method of this invention.

What is claimed is:

l. A phannaceutical composition for treating pain, fever or inflammationcomprising a pharmaceutically acceptable carrier and an effective amountof S-fluoro- 2-methyl- 1 p-methylsulfinylbenzylidene )-3-indenylacetaldehyde.

2. A method of treating pain, fever or inflammation which comprisesadministering to a host a therapeutically effective amount of5-fluoro-2-methyl-l-(pmethylsulfinylbenzylidene 3-indenylacetaldehyde.

I. h i i

1. A pharmaceutical composition for treating pain, fever or inflammationcomprising a pharmaceutically acceptable carrier and an effective amountof5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetaldehyde.2. A METHOD OF TREATING PAIN, FEVER OR INFLAMMATION WHICH COMPRISESADMINISTERING TO A HOST A THERAPEUTICALLY EFFECTIVE AMOUNT OF5-FLUORO-2-METHYL-1-(PMETHYLSULFINYLBENZYLIDENE)-3-INDENYLACETALDEHYDE.